Process and intermediates for preparation of 17alpha-acyloxy-6alpha-methylpregn-4-ene-3:20-diones



United States Patent Ofiice 3,004,991 Patented Oct. 17, 1961 7 04, 1 PROCESS IN'I'ERMEDIAIES FOR PREPARA- TION 0F .17a-.ACYLOXY-6,oc-1V1ETHYLPREGN-4- -ElIlL-Z::Zti-DIONES Vladimir Petr-ow, London, England, assignor to The British Drug Houses Limited, London, England, 'a British company NoDr-zwing. FlledSept. 23, 1958, Ser. No. 762,712 "Claimspriority, application Great Britain-Get. 2, 1957 12 Claims. (Cl. 260-3914) This invention is .for improvements in or relating 'to organic compounds and .has particular reference :to the preparation of new 17a-acyloxy 6a-methylpregn-kene- 3:20-diones and their hydrolysis to I7a-hYdIOXY- 6a-1Il6tb ylpregn-4-ene-3 ZO-dione.

Itis an objectof-the present invention to provide new l'la-aoyloxy fia-methylpregn 4 -ene-3; 20'diones '(having the general Formula I below where R'is an acyl group containing up to 10 carbon .atoms) which are of value ,on account of theirprogestational properties. In particular the invention provides the new compounds:

1 7a-caproyloxy-6a-methylpregn-4ene-3 20-di011e, l7a-caproxy-6m-methylpregn-4eene-3 :ZO-dione,

which are of value on account of their proges'tational properties and as intermediates in the preparation of 17ahydroxy-6a-methylpregn-4-ene-3 :20-dione,

17a-hyd1'oxy-6m-methylpregn-4-ene-3 :ZO-dione,

which is of value as .an intermediate in the preparation of biologically active compounds, .such as, for example, the highly .pro gestational 17a-acyl derivatives.

The invention also \provides the following new intermediates:

3,8-acetoxy-17a-hydroxy-6-methy1pregn6-en-20-one,

3B: -17a-diacetoxy 6-rnethylpregn-5-en-20=one,

According to the present invention there'is' provided a process for ihe 'prep'aration of a l7a-acyloxy-6a-"methyl- .ipregn'-4ene-3 :20-dione having the general formula hie {where R an aaeyl group wcoxrtaining .1 to icarbon which process comprises oxidising'a .3,fi=hydroxyor '3fi-acyloxy 6 methylpregna-s l6-dien-20-one having the general formula ,(where R is hydrogen or an 'acyl group containing up to l0 carbon atoms) to the corresponding -16u:l7wepoxide 20 having the general formula (where 'R'is-hydrogen'or an acyl group containing up to 10 carbon atoms), acylating the l-6uzl7a-epo'xide, converting it into a '16;?t-halogeno-l7ez hydroxy derivative by treatment with ,a hydrogen halide, reduetively -dehalogenating the resulting product to a 3fi-aeyloxy-l7u-hyudroxy- '6-methylpregn'-'5-ien-ZO-one having the general formula 3 venient to employ 3fl-acetoxy-6-methylpregna-5:16-dien- 20-one (II; R=Ac) as starting material, the preparation of which has been described in our copending application Ser. No. 755,368. Oxidation of this material to the 160t2170c-6P0Xid6 (III; R=Ac) may be efiected by treating compound II with hydrogen peroxide in an alcoholic solution made alkaline with a hydroxide such as sodium or potassium hydroxide. The reaction proceeds readily at C., but may be accelerated byemploying temperatures up to the boiling point of the alcohol used as solvent. Partial or complete saponification of the BB-acetoxy group may occur during this reaction; acylation, preferably acetylation, of the total product is therefore necessary in order to ensure isolation of pure 3fl-acetoxy- 16a:17a-epoxy-6-methylpreg-n-5-en-20-one (I11; R=Ac) V in reasonable yield.

' latter compound may be achieved by methods well-known to those skilled in the art. Such methods include, for example, treatment of the compound with an acid anhydride and a catalytic quantity of toluene-p-sulphonic acid for several hours at somewhat elevated temperatures. Hydrolysis of the resulting 3fi-acetoxy-17a-acyloxy- 6-methylpregn-5-en-20-one (IV; R=Ac, R=acyl) may best be effected with hotethauolic or methanolic hydrochloric acid, when the 17a-acyloxy-3fl-hydroxy-6-methylpregn-S-en-ZO-one (IV; R=H; R'=acyl) is obtained. Conversion of the latter compound into the required 170:- acyloxy-6a-methylpregn-4-ene-3:20-dione (I; R=acy1) may conveniently be achieved by'an oxidation of the Oppenauer type, employing, for example, toluene as sol- ,vent, cyclohexanone as hydrogen, acceptor, and an aluminium alkoxide in suitable proportions. Careful saponi- 'fication of the foregoing product (I; R=acyl) with, for example, alcoholic alkali furnishes l7a-hydroxy-6a-methylpregn-4-ene-3z20-dione (I; R=H).

Following is adescription by way of example of methods of carrying the invention into effect:

Example 1 3B-acetoxy-6-methylpregna-5:16-dien-20-one (5' g.) in' form) The foregoing epoxide (2 g.) in dioxan(100 ml.) was treated with aqueous hydrogen iodide (17 ml. of 55%) for 30 minutes in the dark. The solids obtained onpouring the mixture into cold water were dissolved in ethanol 150 ml.), and the solution agitated with Raney. nickel sludge (ca. 12 g.) for 30 minutes at room temperature in the dark. The product was isolated with benzene and chromatographed on alumina. Elution with benze'ne and with benzene/ether (1:1) gave material which was crystallised from acetone/hexane. 3p-acetoxy-17othydroxy-6-methylpregn-5-en-20 one formed needles, M.P.

The crude product may then be 4 133 to 134 C., [111 88 (0., 0.22 in chloroform).

The foregoing compound (0.6 g.) was treated with ucaproic anhydride (13 m1.) and toluene-p-sulphonic acid (0.33 g.) for 20 hours at 45 C. Aqueous pyridine was added, the mixture steam-distilled for 1 hour, and the product isolated with ether. Purification from methanol gave 3 8 acetoxy-17a-caproyloxy-G-methylpregn-S-en-ZO- one, needles or plates, M.P. 111 to 112 C., [ul 51 (c., 0.16 in chloroform),

The foregoing ester (420 mg.) was heated underrefiux for 1 hour with methanol (30 m1.) and concentrated hydrochloric acid (2 drops). Concentration invacuo, followed by the careful addition of .water gave '17u-caproyl- 'oxy3B-hydroxy-6-methylpregn-5-en 20oue, needles, M.P.

152 C., [M 59" (c., 0.34 in chloroform).

A solutionof the foregoing compound (300mg) in toluene (6 ml.) and cyclohexanone (9.5 ml.) was treated with aluminium tert.-butoxide (300 mg.) and the mixture refluxed for 30 minutes. After the addition of aqueous Rochelle saltfthe mixture was steam-distilled and the product isolated with chloroform. 17e-caproyloxy-6amethylpregn-4-ene-3:ZO-dione was obtained as crystals, M.'P. to 94 [cal +40 (c., 0.92 in chloroform), k 240 my. (log e=4.18).

A solution of the foregoing compound in methanol (10 ml.) under nitrogen was refluxed whilst potassium hydroxide (70 mg.) in methanol (5 ml.) and water (2 ml.) was added dropwise over 20 minutes, The mixture was refluxed for 2 hours, cooled, .acidified with acetic acid, and the product isolated with chloroform. It crystallised from acetone/hexane to give l7u-hydroxy 6u-methylpregn-4-ene-3z20-dione, prisms, M.P. 220 to 222 C., fab +78 (c., 1.04 in chloroform). Some samples of this compound melted at 264 C., but were otherwise identical (optical rotation and infra-red spectrum) with the lower-melting variety.

7 Example ,2 v

3,8-acetoxy-17a-hydr0xy-6-methylpregn-5en-20-one was prepared as described in Example 1. This compound (1 g.) in benzene (25 ml.) was treated with toluene-psulphonic acid (200 mg.) and capric anhydride (2 ml),

and the mixture heated under reflux for 1 hour. When cool, water was added, the mixture stirred for 2 hours and the product isolated with ether. It was dissolved in methanol (15 ml.) and the solution treated with concentrated hydrochloric acid (2 drops). The mixture was refluxed for 1 hour, cooled, and the product isolated by extraction with ether. It was purified from light petroleum (boiling range 40 to 60) to give needles of 17acaproxy-Sfi-hydroxy-6-methylpregn-5-en-20-one, M.P. C., [111 58 (c., 1.02 in chloroform).

The foregoing compound (0.75 g.) in dry toluene (30 ml.) and cyclohexanone (7 ml.) was treated with aluminium isopropoxide (350 mg.) in toluene (10 ml), and the mixture refluxed for 1 hour; After; theadditionof aqueous Rochelle salt, the'mixture was steamdistilled and the product isolated with ether. Therewas obtained 17o: caproxy-6a-methylpregn-4-ene-3 :20-dione, an oil, I 240 mu (log e=4.18).

Example 3 3p-acetoxy-l7a-hydroxy-6-methylpregn-5-en-20-one (2 g.) (prepared as described in Example 1) in acetic anhydride (20 ml.) was treated with toluene-p-sulphonic acid (1 g.). The mixture was keptat 30 C. for 24 hours, poured into water, and the precipitated solids crystallised from aqueous methanol. 3flzl7a-diacetoxy-6-methylpregn-S-en-ZO-one separated in needles, M.P. 188 to 189 C., [111 76 (c., 1.16 in chloroform).

The foregoing compound (1 g.) in methanol (50 ml.) to-which concentrated hydrochloric acid=(2 drops) had been added, washeated under reflux for l houif. The,

solvent was partially removed in vacuo, and water carefully added. l7u-acetoxy-3fl-hydroxy-6-methylpregna-5- en-20-one crystallised in needles, M.P. 219 to 222 C., [ah-F 72 (c., 0.92 in chloroform).

The foregoing compound (3.4 g.) in toluene (150 ml.) and cyclohexanone '(35 ml.) was heated under reflux, and treated with aluminium isopropoxide (3.4 g.) in toluene (50 ml.). The mixture was refluxed for 2 hours, cooled, aqueous Rochelle salt was added, and the solvents removed by steam-distillation. The solid product was crystallised from acetone/hexane to give l7a-acetoxy-fiumethylpregn-4-ene-3:20-dionie, plates, M.P. 205 to 208 C., [(21 +51 (0., 1.2 in chloroform).

Example 4 3fl-acetoxy-l7u-hydroxy-6-methylpregn-5-en-20-one (l g.) in benzene (25 ml.) was treated with toluene-p-sulphonic acid (200 mg.) and propionic anhydride (1 mil.), and the mixture refluxed for 1 hour. Water was added, the mixture shaken for 4 hours and the product isolated with ether. Crystallisation from hexane gave 3B-acetoxyl7a-propionoxy-(S-methylpregn-5-en-20-one, plates, M.P. 182 0., [M 77- (c., 0.74 in chloroform).

The foregoing compound (4 g.) in methanol (150 ml.) containing 8 drops of concentrated hydrochloric acid was heated under reflux for 1 hour. Addition of water gave 17a-propionoxy-3 ti-hydroxy-6-methylpregn-5-en-20- one, needles, M.P. 170 to 172 C., [04 -'-69 (c., 0.94 in chloroform).

The foregoing compound (1.5 g.) in toluene (60 ml.) and cyclohexanone (14 ml.) was treated with aluminium isopropoxide (1 g.) in toluene (20 ml.) and the mixture refluxed for 1 hour. After the addition of aqueous Rochelle salt, the mixture was steam-distilled and the product isolated with ether. Crystallisation gave l7a-propionoxy-6m-methylpregn-4-ene-3:20-dione, M.P. 154 to 155 C.

Example 5 3fl-acetoxy-6-methylpregna-5:l6-dien-20-one (20 g.) in boiling methanol (250 ml.) was treated with aqueous sodium hydroxide (40 ml. of 40%), followed immediately by hydrogen peroxide (40 ml. of 30%) added dropwise over five minutes. The mixture was refluxed for twenty minutes, poured into water, and the solids collected and purified fi'om aqueous ethanol. lazl7a-epoxy-3fl-hydroxy-G-methylpregn-S-en-ZO-one hydrate formed plates, M.P. 180 to 182 0., [ch 8 (c., 0.94 in chloroform).

The foregoing compound (12 g.) in dioxan (400 ml.) was treated for thirty minutes with aqueous hydrogen iodide (84 of 55%). The mixture was poured into water (3 l.) and the precipitate collected and washed neutral. Its solution in ethanol (500 ml.) was mechanically shaken for thirty minutes with Raney nickel sludge (ca. 120 g.), the nickel removed by filtration and the filtrate taken to dryness under reduced pressure. T rituration of the residue with ether gave a solid which was purified from acetone/hexane. 3fizl7a dihydroxy 6- methylpregn-S-en-ZO-one hydrate formed needles, M.P. 221 to 222 0., [ch 85' (c., 0.95 in chloroform). Acetylation of this compound in pyridine gave 3;;- acetoxy-17u-hydroxy-6-methylpregn-5-en-20-one, needles (firom acetone/hexane), M.P. 133 to 134 0., not depressed in admixture with a specimen prepared as described in Example 1.

I claim:

1. 17a-acetoxy-3phydroxy-6-methylpregn-5-en-20-one.

2. 17a propionoxy 35 hydroxy 6 methylpregn- 5-en-20-one.

3. 17a caproyloxy 3B hydroxy 6 methylpregn- 5-en-20-one.

4. 17a caproxy 3p hydroxy 6 methylpregn- 5-en-20-one.

5. A proces for the preparation of a l7a-acyloxy-6amethylpr'egn-4-ene-3:20-di6n having the general rormula where R is an acyl group derived from aliphatic hydrocarbon carboxylic acid containing up to 10 carbon atoms, which process comprises oxidising a steroid selected from the group consisting of SB-hydroxyand "3pacyloxyb-methylpregna-S:16=dien-20 one having the general formula where R is a group selected from the class consisting of hydrogen and acyl groups derived from an aliphatichydrocarbon carboxylic acid containing up to 10 carbon atoms to the corresponding 16217oz-6POXide having the general formula 7 where R isan acyl group, derived from an aliphatic .hydrocarhonr carboxylic acid containing up to 10 carbon atoms and R is hydrogen, acylating the 17a-hydroxy1 group to give the corresponding 3,8-acyloxy-1h-acyloxy- G-methylpregn-S-en-ZO-one having the general formula IV above and Where R and R are acyl groups derived from an aliphatic hydrocarbon carboxylic acid containing up to 10 carbon atoms, preferentially hydrolysing the 3 ,B- acyloxy group to give 17a-acy1oxy-3B-hydroxy-6-methy1- pregn-S-en-ZO-one and oxidising the latter compound.

6. A process as claimed in claim 5 wherein said 33- acyloXy -6-methy1pregna-5:l6-dien-20-one is oxidised to the corresponding 16a:17a-epoxide by treatment with hydrogen peroxide in alkaline alcoholic solution.

' 7. A process as claimed in claim 5 wherein said l dqglg'l 'epoxide is converted into said 1 fifl-halpgeno fla hydroxyjederivative byitreatment; in a solvent with hydrogeniodide at 'atemperaturelessthan 257 C.- 8.2A;process:as claimed 'inlclaim 5 wherein the reductive dehalogenation is efiected with Raney nickel in ethanol at approximately room temperature. a

'9. A process as claimed in claim 5 wherein acylation of the l7a-hydroxyl group is effected by treatment with an acid anhydride and a catalytic quantity of toluene-psulphonic acid.

10. A process as claimed in claim 5 wherein said 170:- acyloxy-3fl-hydroxy-6-methylpregn-5-en-20-one is subjected to Oppenauer oxidation to provide said 170:- acyloxy-6u-methylpregn-4-ene-3 :ZO-dione.

11. A compound of the formula a 4 Me i 7 wherein R and R are members of the class consisting of hydrogen and acyl radicals, derived from aliphatic hydrocarbon carboxylic acids containing up to 10 carbon atoms. e

12. 3 8 acetoxy- 17a hydroxy 6 methylpregn- 5-en-20--one OTHERREFERENCES' Badcock et al.: J.A.c'.s., v01; 80, pages 29 04 5 (June 9 1 a 

11. A COMPOUND OF THE FORMULA 